P-selectin inhibition enhances thrombus resolution and decreases vein wall fibrosis in a rat model

Myers, Daniel D.; Henke, Peter K.; Wrobleski, Shirley K.; Hawley, Angela E.; Farris, Diana M.; Chapman, Amy M.; Knipp, Brian S.; Thanaporn, Porama; Schaub, Robert G.; Greenfield, Lazar J.; Wakefield, Thomas W.

doi:10.1067/mva.2002.128636

Cited by 43 publications

(34 citation statements)

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“…8 These data, congruent with others, 32,33 suggest that the size of the thrombus is not the main determinant of the vein wall fibrotic response. This has important implications translationally, as current therapies are aimed at decreasing residual thrombus and preventing thrombus extension rather than mediating the molecular response.…”

Section: Discussionsupporting

confidence: 83%

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Low-molecular-weight heparin modulates vein wall fibrotic response in a plasminogen activator inhibitor 1-dependent manner

Obi

Diaz

Ballard-Lipka

et al. 2014

Journal of Vascular Surgery: Venous and Lymphatic Disorders

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Background Treatment with low-molecular-weight heparin (LMWH) favorably alters the vein wall response to deep venous thrombosis (DVT), although the mechanisms remain unclear. Previous studies have suggested that LMWH alters the levels of circulating plasminogen activator inhibitor 1 (PAI-1), a known mediator of fibrosis, and may improve endogenous fibrinolysis. We hypothesized that LMWH favorably alters the vein wall response by binding of PAI-1 and acceleration of fibrinolysis. Methods Wild-type and PAI-1 −/− mice underwent treatment with LMWH after induction of occlusive DVT. Vein wall and plasma were harvested and analyzed by enzyme-linked immunosorbent assay, zymography, real-time polymerase chain reaction, and immunohistochemistry. Results Wild-type mice treated with LMWH exhibited diminished vein wall fibrosis (0.6 ± 0.6 vs 1.4 ± 0.2; P < .01; n = 5) and elevation of circulating PAI-1 (1776 ± 342 vs 567 ± 104 ρg/mL; P < .01; n = 5) compared with untreated controls after occlusive DVT. PAI-1−/− mice treated with LMWH were not similarly protected from fibrosis, despite improved thrombus resolution. Treatment with LMWH was associated with decreased intrathrombus interleukin-lβ (68.6 ± 31.0 vs 223.4 ± 28.9 ρg/mg total protein; P < .01; n = 5) but did not alter inflammatory cell recruitment to the vein wall. PAI-1 −/− mice exhibited significantly elevated intrathrombus (257.2 ± 51.5 vs 4.3 ± 3.8 ρg/mg total protein; n = 5) and vein wall interleukin-13 (187.2 ± 57.6 vs 9.9 ± 1.1 ρg/mg total protein; P < .05; n = 5) as well as vein wall F4/80 positively staining monocytes (53 ± 11 vs 16 ± 2 cells/5 high-power fields; P < .05; n = 4). Conclusions LMWH did not accelerate venous thrombosis resolution but did protect against vein wall fibrosis in a PAI-1-dependent manner in an occlusive DVT model. Lack of PAI-1 correlated with accelerated venous thrombosis resolution but no protection from fibrosis. PAI-1 inhibition as a treatment strategy for DVT is likely to accelerate clearance of the thrombus but may come at the expense of increased vein wall fibrosis. Clinical Relevance The pathophysiologic mechanism of post-thrombotic syndrome is not well understood clinically or experimentally. In this study, we evaluated the effect of the prominent fibrinolytic mechanism, plasminogen activator inhibitor 1 (PAI-1), and low-molecular-weight heparin (LMWH) on vein wall injury after thrombosis. We show here that LMWH is protective from vein wall fibrosis, but this is abrogated in PAI-1-deleted mice. This is also correlated with monocyte vein wall influx. These data support the clinical observation that LMWH may be protective from post-thrombotic vein wall injury in a PAI-1-dependent manner.

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Section: Discussionsupporting

confidence: 83%

“…These data are congruent with other studies reporting that a smaller thrombus does not correlate with a favorable vein wall response. 13,17,32,33 Our results suggest that the beneficial effect of LMWH on the vein wall fibrotic response is independent of thrombus size but dependent on the presence of PAI-1.…”

Section: Discussionmentioning

confidence: 62%

Low-molecular-weight heparin modulates vein wall fibrotic response in a plasminogen activator inhibitor 1-dependent manner

Obi

Diaz

Ballard-Lipka

et al. 2014

Journal of Vascular Surgery: Venous and Lymphatic Disorders

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“…This correlated with a significant decrease in monocyte recruitment at chronic time points. Monocytes are the main cellular players for thrombus resolution, as was previously demonstrated in rodents 4,26 and its significant reduction may contribute to the increased thrombus weights in ApoE-/- mice that were, observed at the most chronic time point.…”

Section: Discussionmentioning

confidence: 58%

Impaired fibrinolytic system in ApoE gene-deleted mice with hyperlipidemia augments deep vein thrombosis

Díaz

Ballard-Lipka

Farris

et al. 2012

Journal of Vascular Surgery

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Background Hyperlipidemia increases the level of blood plasminogen activator inhibitor-1 (PAI-1) that is responsible for regulating fibrinolysis by inhibiting both urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA). While this fibrinolytic pathway is well known, the role of PAI-1 in venous thrombosis (VT) in hyperlipidemic conditions has not been fully established. We sought to determine the effects of PAI-1 in an in vivo hyperlipidemic model of VT. Method C57BL/6 wild type (WT) mice, Apolipoprotein E gene-deleted mice (ApoE-/-), having hyperlipidemia, and PAI-1 gene-deleted (PAI-1-/-) mice were used in this study. Inferior vena cava (IVC) ligation below the level of the renal veins was performed to create a stasis VT. Endpoints included measuring acute thrombosis (day 2) and chronic thrombosis (days 6 and 14). At euthanasia, blood samples were collected for plasmin activity, and PAI-1 activity. In addition, the IVC and its thrombus were evaluated for thrombus weight (TW), u-PA activity, differential leukocyte count while the vein wall only was analyzed for monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase (MMP) 2 and MMP-9. Results Compared to WT at day 2, ApoE-/- mice demonstrated a statistically significant increase by 14% in TW (P<.05), and a significant 41% increase in circulating PAI-1 activity (P<.05), while showing a trend of decreased plasmin activity. In addition, TW in ApoE-/- mice was 45% higher than PAI-1-/- mice at day 2 (P<.05), 33% at day 6 (P<.01) and 41% at day 14 (P<.01). ApoE-/- mice exhibited undetectable levels of u-PA in both vein wall and thrombus, compared to WT, at all time points. Also, vein wall MMP-2 was significant decreased by 64% at day 6 (P<.01) and 58% at day 14 (P<.05). MMP-9 was significantly decreased by 71% at day 2 (P<.01) and 48% at day 6 (P<.01), in ApoE-/- mice compared to WT. In addition, in ApoE-/- mice, MCP-1 was significantly decreased by 38% at day 2 (P<.01) and 67% at day 6 (P<.01), versus WT mice. As expected in ApoE mice, following a decrease in MCP-1, monocyte recruitment was significantly decreased at days 6 (P<.01) and 14 (P<.05). Conclusions A significant increase of circulating PAI-1 levels, in hyperlipidemic mice, correlated with an early increase in TW, due to impaired fibrinolysis. The undetectable levels of u-PA in ApoE-/- mice correlated to a decrease in vein wall MMP-2, MMP-9, MCP-1 and a decrease in monocyte recruitment diminishing thrombus resolution.

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“…36 Indeed, the importance of P-selectin in stasis-induced experimental DVT resolution has been reported. 37 In addition, we observed that stenosis-induced thrombosis was decreased in P-selectin knockout mice although to a lesser extent than in VWF Ϫ/Ϫ mice (S.M., unpublished data, 2009). However, GPG-290, which efficiently prevented flow restriction-induced thrombosis in WT mice, did not exert any effect on P-selectin-mediated leukocyte rolling.…”

Section: Discussionmentioning

confidence: 90%

von Willebrand factor–mediated platelet adhesion is critical for deep vein thrombosis in mouse models

Brill

Fuchs

Chauhan

et al. 2011

Blood

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Deep vein thrombosis (DVT) and its complication, pulmonary embolism, are frequent causes of disability and mortality. Although blood flow disturbance is considered an important triggering factor, the mechanism of DVT initiation remains elusive. Here IntroductionAnnually, approximately 900 000 people in the United States suffer from deep vein thrombosis (DVT) and its life-threatening complication, pulmonary embolism. 1 Although various risk factors predisposing to DVT have been clinically identified, mechanisms of thrombus initiation remain unclear. The classic Virchow triad attributes an important role in thrombosis to the combination of blood flow restriction, hypercoagulable state of the blood, and prothrombotic changes in the vessel wall. In contrast to arterial thrombosis, which usually starts from platelet adhesion to the exposed subendothelial matrix or ruptured atherosclerotic lesion, in DVT, the endothelial layer shows no major damage. 2 In accordance with this triad, disturbances of blood flow and stasis in veins are considered major pathogenic factors of DVT, 3 and several hereditary procoagulant conditions, such as prothrombin G20210A mutation, 4 deficiency in protein C, 5 or resistance to activated protein C 6 due to Factor V Leiden mutation, 7 are associated with an increased risk of DVT. However, disturbed blood flow may be a dominant factor as it can provoke DVT as a result of long-term immobilization without marked blood hypercoagulability. 8,9 It is known that hypoxia activates endothelium, promotes Weibel-Palade body (WPB) release, and facilitates blood coagulation. 10,11 It has been hypothesized that hypoxia-induced expression of P-selectin, an adhesion receptor stored in WPBs, on the endothelial surface may recruit tissue factor-rich microparticles, thus initiating thrombus development. 12 Indeed, endothelial cells in the inferior vena cava (IVC) rapidly express P-selectin from WPBs and recruit tissue factor in stasis-induced DVT in rats. 13 Whether flow disturbance per se without complete occlusion can induce release of WPB constituents remains unknown.WPBs also contain von Willebrand factor (VWF), a multimeric protein mediating platelet adhesion to the vessel wall and platelet recruitment to the growing thrombus. 14 VWF is released as a large multimer, 15 which is then cleaved by a plasma enzyme, 16,17 now designated as a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13), 18,19 to smaller molecules with lower prothrombotic activity. The A1 domain of VWF binds the platelet glycoprotein Ib␣ promoting platelet adhesion and incorporation in a developing thrombus. The key impact of VWF in arterial thrombosis has been repeatedly demonstrated, and more recently the role of VWF in platelet plug formation in injured venules was reported. 20 However, whether VWF plays a role in platelet recruitment in DVT remains elusive.In the present work, we investigated whether platelet interaction with VWF expressed on the endothelium as a result of flow restriction plays ...

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P-selectin inhibition enhances thrombus resolution and decreases vein wall fibrosis in a rat model

Abstract: rPSGL-Ig, LMWH, and tPA showed equal DVT resolution efficacy over 7 days. However, only rPSGL-Ig was associated with a decrease in vein wall fibrosis, suggesting that purely accelerating DVT resolution may not decrease long-term vein scarring.

Cited by 43 publications

References 32 publications

Low-molecular-weight heparin modulates vein wall fibrotic response in a plasminogen activator inhibitor 1-dependent manner

Low-molecular-weight heparin modulates vein wall fibrotic response in a plasminogen activator inhibitor 1-dependent manner

Impaired fibrinolytic system in ApoE gene-deleted mice with hyperlipidemia augments deep vein thrombosis

von Willebrand factor–mediated platelet adhesion is critical for deep vein thrombosis in mouse models

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